The DNA Network

Do you hear that sound Mr Anderson? [The Gene Sherpa: Personalized Medicine and You]

Posted: 16 Jun 2008 12:13 AM CDT

In an obvious move California has taken their stance. This was the sound of inevitability. I find it funny that the same journalist hyping these tests 1 year ago is now reporting on how California...

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Equal opportunity genomics [Genetic Future]

Posted: 15 Jun 2008 06:10 PM CDT

ScienceDaily reports a bold strike against the human genomics patriarchy:

Geneticists of Leiden University Medical Centre (LUMC) are the first to determine the DNA sequence of a woman.

Well, there are other female genomes out there - the 1000 Genomes Project has already generated moderate-coverage sequence for at least one female (an anonymous woman of European ancestry, collected in Utah) and low-coverage sequences of perhaps half a dozen more, and I think the Cancer Genome Project has sequenced at least one tumour sample from a female patient - but perhaps Leiden beat them to it, and at the very least they can legitimately claim to be the first to realise that the gender of a genome donor by itself was enough to warrant publicity.

Public relations aside, there's nothing hugely biologically interesting about sequencing a female genome - it just means you get one extra copy of the X chromosome. As the article notes, that does give us a little bit of extra information about the genetic diversity on this exquisitely interesting chromosome, but I'm not sure to what extent this outweighs the extra information you could get from sequencing a male (Y chromosome sequence, and accurate information about the precise arrangement of variations along the X chromosome - information that is "scrambled" when you sequence two copies at once).

The article is more interesting in what it says about the sudden explosion in sequencing capacity resulting from next-generation sequencing technologies:

"The sequencing itself took about six months. Partly since it was run as a 'side operation' filling the empty positions on the machine while running other projects. Would such a job be done in one go, it would take just ten weeks".

That's right - they sequenced an entire human genome using just the left-over capacity of their sequencing machines, in six months. This sort of capacity certainly isn't limited to Leiden: sequencing facilities around the world are all churning out human genome equivalents every few days. Now, consider that the first human genome took the combined work of hundreds of scientists from over 18 countries for thirteen years, and you have you a taste of how rapidly sequencing technology is moving.

I wonder how many more "first" human genomes we'll be expected to applaud over the next few months. Already this year we've had the first Nobel prize-winning genome, the first African genome and the first East Asian genome announced. Next, I suppose we'll have a spate of disease genomes: the first cancerous genome of course, but also perhaps the first autistic genome, the first obese genome, the first arthritic genome...

None of them will mean much by themselves; the exciting results will come when this exploding sequencing capacity allows researchers to compare the whole genomes of thousands of disease patients with those of thousands of controls. These studies are approaching rapidly, and in addition to their powerful information they'll bring a host of technical challenges in terms of sequence generation, data storage and transfer, and interpretation. I'll be talking a lot more about the promises and challenges of next-generation sequencing over the next couple of months - stay tuned.

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California cracks down on genetic testing companies [Genetic Future]

Posted: 15 Jun 2008 06:09 PM CDT

California has sent cease-and-desist letters to 13 direct-to-consumer genetic testing companies, "ordering them to immediately stop offering genetic tests to state residents". The companies haven't been named yet, although Navigenics has admitted to being among them, and is arguing that they are doing nothing wrong. Steve Murphy of Helix Health, who has been calling for tighter regulation of these companies for months, is predictably triumphal.

Naturally, this is just the beginning - to a large extent what's going on here is a turf war between proponents of the old-school medical regulation model and upstart advocates of the free information paradigm of the Google generation. Expect to see more regulatory punches thrown over the next few months, to Steve's continued delight.

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The adaptive origins of attention deficit disorder [Genetic Future]

Posted: 15 Jun 2008 06:09 PM CDT

Razib from Gene Expression describes a potentially fascinating study on a variant of the DRD4 gene, which was first shown to be associated with attention deficit hyperactivity disorder (ADHD) more than ten years ago. (It's worth emphasising, by the way, that DRD4 is just one of the many genes likely to be involved in this complex trait). Interestingly, the same variant has also been reported to show a signature of recent positive selection in some human populations, suggesting that the behavioural "problems" displayed by modern individuals with ADHD may actually result from a mis-match between the environment our hunter-gatherer ancestors were adapted to and the bizarre, restrictive environment of Homo suburbanensis.

The full article hasn't actually been released yet, so we're all forced to play the now-familiar game of "science by press release" based on an article in ScienceDaily. Apparently, researchers directly tested the mis-match hypothesis by looking at the effects of the ADHD version of the gene on body mass index, a crude measure of nutrition levels, in men from the Ariaal tribe in Kenya. Some of the members of this tribe are nomadic while others live in settled communities. In agreement with the predictions of the mis-match hypothesis, those with the ADHD version of DRD4 were fatter (i.e. healthier) in nomadic populations, but skinnier (unhealthier) in settled groups.

The explanation of the results by the study's lead author:

"The DRD4/7R allele [i.e. the ADHD version of the gene] has been linked to greater food and drug cravings, novelty-seeking, and ADHD symptoms. It is possible that in the nomadic setting, a boy with this allele might be able to more effectively defend livestock against raiders or locate food and water sources, but that the same tendencies might not be as beneficial in settled pursuits such as focusing in school, farming or selling goods".

In other words, behaviour that would result in a rapid trip to the headmaster (followed by the psychiatrist) in stable, industrialised society may actually have been extremely useful in the relatively uncertain world of the hunter-gatherer tribesman.

Of course, simply knowing that ADHD is "natural" doesn't necessarily make it any easier to solve the broader problem of how society should be dealing with individuals with ADHD. In an ideal world, education would be tailored to the unique learning demands of individual students, resulting in the maximisation of each child's potential skills. However, in a world with limited resources for education, is society's current approach (medicate them until they shut up and learn like the other kids) the only workable solution? Or can we figure out a way to restructure society such that "obsolete" ADHD tendencies become useful again?

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The 1000 Genomes Project: battle-ground for next-gen sequencers [Genetic Future]

Posted: 15 Jun 2008 06:09 PM CDT

The 1000 Genomes Project is an ambitious international venture, launched back in January, that seeks to leverage advances in DNA sequencing technology to create a map of human genetic variation with unprecedented resolution.

The formal scientific goal of the project is "to produce a catalog of [genetic] variants that are present at 1 percent or greater frequency in the human population across most of the genome, and down to 0.5 percent or lower within genes". This will involve the generation of mind-boggling amounts of sequence data: according to Paul Flicek from the European Bioinformatics Institute, who has been coordinating data storage and transfer for the project, the final data-set will probably take up close to 1 Pb (i.e. one million gigabytes)!

The scale of this project has only become feasible over the last year or two with the appearance of so-called "next-generation" sequencing platforms: new technologies that are capable of reading billions of bases of DNA in a single run, over just a few days. Although the field is rapidly heating up, right now there are three commercial platforms in the market: the 454 system provided by Roche, Applied Biosystem's SOLiD technology, and Illumina's Genome Analyzer (previously known as Solexa). Each of the platforms has its positive and negative points, but those aren't relevant for this post: suffice it to say that there is currently a serious arms race between these three products, with each of the respective companies eyeing the lucrative medical sequencing market just around the corner.

This arms race appears to be great news for the 1000 Genomes Project. As an Applied Biosystems press release spells out today, the major companies are literally giving away sequencing capacity to the Project in return for product exposure - all three of them have now committed to sequencing 75 billion bases, the equivalent of sequencing a complete human genome 25 times over. In the press release, Project steering committee co-chair Richard Durbin says:

"It is a win-win arrangement for all involved. The companies will gain an exciting opportunity to test their technologies on hundreds of samples of human DNA, and the project will obtain data and insight to achieve its goals in a more efficient and cost-effective manner than we could without their help."

The stakes are extremely high here. Involvement in the 1000 Genomes Project gives these companies an opportunity to prove their technology to the researchers in major sequencing facilities who will ultimately be some of their biggest customers, while at the same time providing some valuable public relations stories - Illumina got some good coverage with their "first African genome" back in February, for instance. The platforms that can prove themselves early in the game will have a serious edge over later competitors, simply by being well-established in the large facilities by the time young upstarts like Pacific Biosciences even have a product on the market. And when you think about just how much money there will be in the medical sequencing business within the next few years, Durbin's "exciting opportunity" starts to seem like classic British understatement.

Anyway, you can expect things to get pretty serious over the next few months, as the involvement of all three of the platforms in the 1000 Genomes Project (both as providers of free sequence, and in terms of machines in the participating facilities) provides a level playing field for comparing the throughput, accuracy, ease of use and running costs of the three competitors, engaged in the sequencing activity that matters the most right now: assembling entire genomes from human beings, as cheaply, accurately and quickly as possible.

Meanwhile, those of us interested in personal genomics get to sit back and watch the fireworks, knowing that it doesn't really matter who wins this race - so long as it's being run, our genome sequences are becoming steadily more affordable.

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Brain scanning vs personal genomics [Genetic Future]

Posted: 15 Jun 2008 06:08 PM CDT

Personal genomics companies like 23andMe, deCODEme and Navigenics have taken substantial media flak recently over their limited ability to make useful disease risk predictions based on genome scan data.

There's certainly some truth to that accusation, but all three of these companies have been generally good at conveying this uncertainty to their customers. In particular, I've been amazed by the tendency of deCODEme to play down the usefulness of their tests in terms of disease prediction. I've previously mentioned deCODE's Kari Stephansson's admission at Cold Spring Harbor Laboratory that deCODEme is "marketing these tests without any claim that they will impact on people's lives"; a couple of weeks ago I attended a seminar on personal genomics in Cambridge, UK, where deCODEme's Agnar Helgason volunteered that "what we can offer at the moment is pretty meagre". Navigenics and 23andMe tend to avoid such frank admissions, but their predictions are still very carefully phrased in statistical terms.

In any case, the accuracy of predictions based on personal genomics starts to look much more impressive when it's compared to some of the other 'science-based' prediction industries out there. A recent article in Wired has a fairly scathing review of one such field: the use of functional brain scans to predict risks of mental illness, personality traits, dishonesty, political views and consumer behaviour.

Given the $3,300 price tag for one of the services on offer (from a company that is "dedicated to optimizing the brain-life connection in our patients and people worldwide", according to their website), this is a pretty expensive piece of foolishness. No doubt some patients benefit from the service, but it's likely that they would have gained just as much from a visit to a good counsellor without the fancy brain scans, at a small fraction of the cost.

Long-term readers will know that I don't recommend current genome scans - my suggestion is that potential customers save their money for a few years, by which time large-scale sequencing will be affordable, and we will know much more about disease-associated genetic variants - but if I had to pick a fancy technology to waste my money on I'd go with a genome scan over a brain scan any day.

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Free personal genomics! [Genetic Future]

Posted: 15 Jun 2008 06:07 PM CDT

Over at Eye on DNA, Hsien wonders about the effects of a slowing economy on the personal genomics market. Well, no matter how hard it's getting to make your mortgage repayments, you can probably still afford personal genomics if it doesn't cost you anything:

In New Jersey, meanwhile, the nonprofit Coriell Institute for Medical Research is developing a service that will test for a slate of validated genetic markers, and provide free — yes, free — information and analysis for common diseases. The institute plans to sign up 10,000 people in the next two years, and eventually enlist 100,000 people.

(From a recent piece in Wired). You can sign up here; there is a pretty extensive FAQ here. Note that you will need to physically attend an enrollment session at the Coriell Institute in New Jersey. Also, I see that Coriell is adopting the paternalistic "need to know" approach pioneered by Navigenics, and won't provide participants with any information about genetic variants that aren't "medically actionable" (e.g. incurable disease risk variants), although they will hand out information on non-disease traits like eye colour. Still, if I lived anywhere near New Jersey I'd be signing up right now rather than wasting time writing this post.

(As an aside, I wonder why Coriell is using a saliva-based method when it could be using its considerable expertise to create and store cell lines from blood - essentially generating an endless source of DNA for researchers to analyse. That seems like a missed opportunity that someone will be seriously regretting in a few years when there's no DNA left for whole-genome sequencing, or epigenome analysis, or whatever.)

If you're more ambitious, you could also sign up for (eventual) free genome sequencing via the Personal Genome Project.

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Future of Microbiology Funding at NSF? [The Tree of Life]

Posted: 15 Jun 2008 04:21 PM CDT

Just got pointed to slides from Jim Collins' recent talk at the ASM Meeting in Boston (Collins is the Assistant Director of the NSF Directorate for Biological Sciences) . Unfortunately, I missed his talk but you can get a PDF file of his slides (with proprietary ones removed) and it makes for some interesting viewing.

There are clearly some big changes planned at NSF for "microbial" research and there seems to be a plan to merge what used to be microbe focused projects into other programs such as NEON, Assembling the Tree of Life, and others. There do appear to be some "Microbe" specific programs that will still be around including a new one "Microbial Systems in the Biosphere" which seems to be replacing/merging with the Microbial Genomes and the Microbial Observatories program.

Anyway ... it seems that some changes are afoot at NSF. Since I missed the talk it is hard to tell what the general plan and big picture is here. If anyone out there went to his talk or have seen other talks of his it would be useful if you could post some impressions here.

Where I've Been the Past Couple Weeks [evolgen]

Posted: 15 Jun 2008 02:00 PM CDT

If you check the archives of this blog (which I know all of you do on a fairly regular basis), you'll see that I haven't posted anything in over two weeks. Those kind of blog hiatuses can't be good for traffic, but I have a legitimate excuse: I was out of the country. Readers with a keen eye for international architecture will recognize the picture attached to this post. Those without, may not. Either way, I figure I should tell you that it's one of the facades of Sagrada Familia, Antoni Gaudi's best known unfinished church.

Why post a picture of this famous tourist spot? Because I was in Barcelona for the SMBE meeting last week. I met up with John Logsdon (among many other people), and apparently John Dennehy was as well. It was an excellent conference, as SMBE meetings usually are. My only complaint: too many sessions that I wanted to attend that were scheduled concurrently.

Anyway, I intend to blog about a couple talks that I attended that discussed some interesting published results. I may also blog about some other Barcelona/SMBE stuff if the spirit fills me.

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A million minds getting together can be confusing but might end up being really cool [The Tree of Life]

Posted: 15 Jun 2008 07:10 AM CDT

Their is a possibly interesting paper in Genome Biology by Barend Mons et al: Calling on a million minds for community annotation in WikiProteins. I say possibly because the paper itself is quite confusing to me but the overall goal seems to be a cool concept. This group has created and is encouraging the use of "WikiProteins" a community annotation system for "community knowledge." Sounds a bit fuzzy? Well, reading the paper does not completely help. For example here is the abstract

WikiProteins enables community annotation in a Wiki-based system. Extracts of major data sources have been fused into an editable environment that links out to the original sources. Data from community edits create automatic copies of the original data. Semantic technology captures concepts co-occurring in one sentence and thus potential factual statements. In addition, indirect associations between concepts have been calculated. We call on a 'million minds' to annotate a 'million concepts' and to collect facts from the literature with the reward of collaborative knowledge discovery. The system is available for beta testing at http://www.wikiprofessional.org webcite.

I got really lost reading this I confess. But I moved on since the overall concept seemed quite intriguing, even if I did not get it completely. But it did not get much clearer further on. For example consider their description of a "knowlet"

The future outlook to integrate data mining (for instance gene co-expression data) with literature mining, as formulated in the review by Jensen et al. [2], is at the core of what we aim for at the text mining/data mining interface. To support the capturing of qualitative as well as quantitative data of different natures into a light, flexible, and dynamic ontology format, we have developed a software component called Knowlets™. The Knowlets combine multiple attributes and values for relationships between concepts.

Scientific publications contain many re-iterations of factual statements. The Knowlet records relationships between two concepts only once. The attributes and values of the relationships change based on multiple instances of factual statements (the F parameter), increasing co-occurrence (the C parameter) or associations (The A parameter). This approach results in a minimal growth of the 'concept space' as compared to the text space (Figure 1).

OK ... I got lost every time I tried to read this in detail. I do think they could benefit greatly by translating their paper from the language used by people who work on text mining to a broader presentation.

But reading between the lines here, this is a new, apparently open access system to try and get community annotation for "Concepts" and for relationships among concepts in biological sciences. Those concepts could include a wide range of things, including genes, genomes, proteins, as well as more standard concepts like functions. Whatever this system is, it seems worth checking out.

I leave you with their ending:

Once widely used and augmented, this resource could become an open, yet quality assured and comprehensive, environment for collaborative reference and knowledge discovery.

Now that I can say I understand and it sounds good to me. If anyone out there has any more insight into this, please give your input.